Study design
This prospective randomized blinded study was conducted at the Veterinary Teaching Hospital of the University of Pisa. The study received approval by the Ethical Committee for animal welfare of University of Pisa (n = 22/2020), and the study included dogs undergoing orthopedic surgery. All methods were carried out in accordance with relevant guidelines and regulations for studies involving animal and in accordance with ARRIVE guidelines. The study did not involve humans.
Animals
To identify a difference of at least 120 minutes between the 2 groups, the median duration of nerve blocks was estimated at 480 minutes, and an α error of 0.05 and a β error of 0.2 were used; the minimum number of dogs necessary for each group was 7. To account for higher than expected values, standard deviations and data loss of up to 30%, the number of dogs in each group was increased to 10.
All dogs had a complete physical examination and full bloodwork (complete blood count, plasma biochemistry panel, and coagulation test) at hospital admission.
The exclusion criteria included a C-reactive protein (CRP) level > 0.3 mg dL− 1, an albumin concentration < 2.00 g dL− 1, a dog > 13 years of age, a diagnosis of malignancy, an aggressive disposition, skin infections, or the inability to secure vascular access before premedication.
Study protocol
All dogs were randomly divided into two groups according to the use of an online software program (random.org): the dexmedetomidine group (DEX) and the saline group (NaCl). The dexmedetomidine group received a CRI of dexmedetomidine at 1 mcg kg− 1h− 1, while the control group received an equivalent volume infusion of 0.9% saline solution. The infusion syringes, which were only labeled with the patient identification number, were prepared by an operator not directly involved in the study. On the day of surgery, a peripheral venous catheter was placed (cephalic or saphenous) to facilitate CRI administration. The CRIs (dexmedetomidine or saline) were started 10 minutes prior to anesthetic induction and discontinued at the end of anesthesia. Ten minutes after the start of the CRI, all dogs received 0.2 mg kg− 1 IV methadone (Semfortan, 10 mg mL− 1; Dechra, Turin, Italy) and were induced with propofol (Proposure, Boehringer Ingelheim Animal Health, Italy S.p.A.) to achieve orotracheal intubation. Patients were connected to an anesthetic machine (Avance CS2 Pro, GE, Milan, Italy) by a rebreathing system and maintained on isoflurane (Vetflurane, Virbac S.r.l., Milan, Italy) in oxygen at an inspired fraction of 70%.
All patients were ventilated using volume-controlled settings with a tidal volume of 10 mL kg− 1 and a variable respiratory rate targeted to maintain an end-expiratory carbon dioxide (PE’CO2) value between 35 and 45 mmHg. To combat intraoperative atelectasis, positive end-expiratory pressure (PEEP) was set at 5 cm H2O.
Patients were positioned in lateral recumbency with the target leg to block in the nongravity-dependent position, and after trichotomy and surgical resection of the region, nerve blockade was performed. Ultrasound-guided sciatic, saphenous and obturator nerve blocks were performed as previously described14–16 using 0.1 mL kg− 1 0.5% ropivacaine (Naropina; AstraZeneca, Verona, Italy). All blocks were performed using an in-plane visual axis technique17 with a dedicated echogenic needle (Visioplex, Vygon Italia S.r.l., Padua, Italy) and a linear transducer (HFL50, 15–6 MHz Linear Transducer). Operators performing blocks and clinicians monitoring patients throughout the intra- and postoperative periods were blinded to the study CRI administered.
In the event nociception was suspected based on an increase in heart rate and/or mean arterial pressure (MAP) greater than 15% above previous measurements18, a bolus of fentanyl 1 mcg kg− 1 (Fentadon, 50 mcg mL− 1, Eurovet Animal Health B.V., Bladel, The Netherlands) was administered, and if considered insufficient, a variable dose of fentanyl CRI was initiated. If dogs experienced hypotension (MAP < 70 mmHg), dopamine (Dopamina Hospira, 200 mg mL− 1; Hospira Italia, Naples, Italy) was administered, which was replaced by norepinephrine (Noradrenalina tartato 2 mg mL− 1; S.A.L.F.). S.p.A. Bergamo, Italy) if dopamine failed to correct the hypotension within 5 minutes.
During surgery, heart rate (HR), arterial blood pressure, capillary refill time (CRT), ECG rhythm, end-tidal CO2 (PE’CO2), fraction of expired isoflurane (Fe’Iso) and spirometry were recorded every five minutes (Avance CS2 Pro, GE, Milan, Italy) and at specific surgical time points (Table 1). The dexmedetomidine or NaCl CRI was discontinued when inhalant anesthesia was stopped. The need and dose of any analgesic (fentanyl) and/or vasoactive drugs (dopamine, norepinephrine) administered were also recorded. Postoperative pain was assessed every hour starting from the time of extubation using the Glasgow Composite Pain Scale (GCPS); if the pain score was greater than 6 of 24 or 5 of 20, methadone was administered at 0.2 mg kg− 1 IM (Semfortan, 10 mg mL− 1; Dechra, Turin, Italy), and carprofen was administered at 2 mg kg− 1 IV (Rimadyl, 50 mg mL− 1; Zoetis Italia S.r.l., Rome, Italy).
Table 1
Data recording time points
Time | | Procedure |
T0 | five minutes prior to surgical draping |
T1 | surgical draping |
T2 | skin and subcutaneous tissue incision |
T3 | drilling |
T4 | tibial osteotomy |
T5 | plate fixation |
T6 | skin and subcutaneous tissue closure |
The postoperative analgesic requirements and possible side effects and complications during hospitalization and at the surgical follow-up were recorded.
Statistical analysis
The data were analyzed for normality using D'Agostino and Pearson tests and a commercial software program (Prism 9; GraphPad Prism, Inc.). Parametric data are expressed as the mean and standard deviation, while nonparametric data are expressed as the median and range. Student's t test and the Mann‒Whitney test were used to compare parameters between groups. One-way ANOVA with Dunnett's post hoc test was used to compare values within groups over time. A chi-square test was used to compare groups requiring rescue analgesia and vasopressors. P values < 0.05 were considered to indicate statistical significance.